Development of transgenic rabbits as models for atherosclerotic research

为了研究动脉粥样硬化，我们在1998年底成功培育了表达人载脂蛋白(a) [Lp(a)]或脂蛋白脂肪酶（LPL）的转基因兔子。载脂蛋白(a)转基因家兔：移植到养母体内共获得93只幼兔。11只兔子的基因组中发现了转基因。3只转基因家兔出生后不久，5只转基因家兔血浆中没有检测到载脂蛋白(a)的表达。建立了3个转基因家兔系；A01组血浆载脂蛋白为1.8mg/dl， A46组为3.4 mg/dI， A47组为4.5 mg/dl。对A10系进行F1和F2选育，得到如下结果：人载脂蛋白(a) mRNA主要表达于肝脏和肾脏。转基因家兔血浆载脂蛋白(a)在β前位置表现出与人Lp(a)相似的移动性。在转基因家兔血浆中，与转基因小鼠血浆不同的是，约80%的载脂蛋白(a)与兔载脂蛋白b共价结合，存在于密度为1.02 ~ 1.10 g/ml的组分中，说明Lp(a)的形成。这些结果表明，表达人载脂蛋白(a)的转基因家兔能够高效地组装Lp(a)，可以作为研究人Lp(a)的动物模型。现在，我们已经开始通过喂养富含胆固醇的饮食来培养更多的F1用于动脉粥样硬化的研究。LPL转基因家兔：目前，我们已经培育出3只鸡b-肌动蛋白启动子控制的LPL转基因家兔和4只清除率受体启动子控制的LPL转基因家兔。目前正在对这些转基因兔子进行鉴定。

For the study of atheroslerosis, we have successfully generated transgenic rabbits expressing either human apolipoprotein(a) [Lp(a)] or lipoprotein lipase (LPL) at the end of 1998.Apo(a) transgenic rabbits :Totally, 93 pups were obtained after transplantation into foster mothers. 11 rabbits were found to have transgene integrated into their genome. 3 transgenic rabbits soon after birth and 5 transgenic rabbits show no detectable expression of apo(a) in the plasma. 3 transgenic rabbit lines have been established ; A01 line has 1.8mg/dl, A46 line has 3.4 mg/dI, and A47 line has 4.5 mg/dl of apo(a) in the plasma. A10 line has been bred into F1 and F2 and the following results were obtained. Human apo(a) mRNA expression was mainly found in the liver and kidney. Plasma apo(a), in transgenic rabbits showed a similar mobility to human Lp(a) at pre-beta position. In the plasma of transgenic rabbits, unlike the plasma of transgenic mice, about 80% of the apo(a) was covalently associated with rabbit apo-B and was contained in the fractions with density 1.02-1.10 g/ml, indicating the formation of Lp(a). These results suggest that transgenic rabbits expressing human apo(a) exhibit efficient assembly of Lp(a) and can be used as an animal model for the study of human Lp(a). Now, we have started to breed more F1 for the study of atherosclerosis by feeding cholesterol-rich diet.LPL transgenic rabbits :Until now, we have produced 3 LPL transgenic rabbits under the control of chicken b-actin promoter and 4 LPL transgenic rabbits under the control of scavenger receptor promoter. Characterization of these transgenic rabbits are currently underway.